3. Association of 13-CA repeat allele of IFN gamma intron 1 polymorphism with development of IgA nephropathy

Abstract: IgA nephropathy (IgAN) is a disorder related to an abnormal immune response which is characterized by increased synthesis of deglycosylated IgA1. T helper (h) lymphocytes in pathogenic immune response at mucosal effector site have been shown to play a key role in IgAN. The cytokine levels themselves have the most critical role in Th cell polarization. We considered cytokine gene polymorphisms, which in turn influence the production of the respective cytokines.

The following gene polymorphisms were analysed:
- Interferon (IFN) gamma intron-1 CA-repeat at position 13491373 (Capillary electrophoresis) for Th1-type cytokine;

- Interleukin (IL)-13 1055C/T (SSCP) for Th2;

- Transforming growth factor (TGF) beta 915G/C (SSCP) for Th3; IL-10 5-proximal and distal microsatellites (PAGE) for TR;

- Tumor necrosis factor (TNF) alfa -308G/A (RFLP/NcoI), -238G/A (RFLP/BglII) for monocytes/macrophages.

We carried out a family-based association study on 50 families, which included 53 IgAN patients, 45 complete trios, 4 incomplete trios and 36 discordant siblings. Statistical analysis was performed using the family-based association test (FBAT) software freely available from: http://www.biostat.harvard.edu/~fbat/default.htlm. It incorporates a set of statistical procedures to accommodate variable pedigree constellations, dichotomous or quantitative phenotypes, phenotype-unknown subjects, bi- or multi-allelic marker data, multiple loci and various models for the mode of inheritance and gene-environment interactions. Moreover, genotyping of IFNg intron-1 microsatellite was carried out in a cohort of 174 IgAN patients to evaluate the influence on disease outcome of the seven alleles identified in our population.

Multi-allelic analysis showed the association between IFNg polymorphism and susceptibility to IgAN (p=0.03). No significant association was found between other cytokine gene polymorphisms and the disease. The bi-allelic analysis, to evaluate how the seven different IFN gamma alleles influenced the disease, evidenced that the 13-CA repeat allele was preferentially transmitted to the affected individuals (p=0.006). Association between the presence/absence of risk genotype and gender, age at onset of the disease and at the time of renal biopsy, serum creatinine and renal function, daily proteinuria progressively increasing, and histological lesions did not yield significant results. In addition, 163 out 174 patients of the cohort with a mean follow-up of 5 years (range 1-30 years) were distinguished as progressors (46) and non-progressors (117). Progressor patient was defined as one who reached end stage renal disease (ESRD) or had a serum creatinine (sCr) value, which doubled from the time of renal biopsy. Progression was observed in 42.4% of 13 CA-repeat allele carriers versus 57.6% of non-carriers. No significant difference in IFN gamma 13 CA-repeat allele distribution between these two groups was found (p= 0.72). No association with disease progression was found.

A correlation of 12-CA repeat IFN gamma allele and a higher cytokine production has previously been demonstrated by in vitro assays. In our IgAN patient population 12-CA and 13-CA repeat IFNg allele distribution was 43.4% and 44.3%, respectively. We can conclude that the association between 13-CA repeats IFN gamma allele as a lower producer genotype status and IgAN development could be suggestive of a predominance of the Th2 immune response. A relative or absolute increase in Th2 cytokine production is a significant pathogenic factor in human IgAN since it may lead to abnormalities in IgA1 glycosylation and formation of circulating IgA1-IgG (anti IgA1) immunocomplexes.

This is the first and largest to date family-based study, which suggests an important role of IFN gamma in the development of the disease.

Back     Previous result     Next result